This invention relates to spirotricyclic substituted azacycloalkane derivatives and pharmaceutically acceptable salts thereof, their synthesis, and their use as alpha 1a adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating benign prostatic hyperplasia (BPH).
References are made throughout this application to various publications, the disclosures of which are hereby incorporated by reference in their entireties, in order to more fully describe the state of the art to which this invention pertains.
Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine.
Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla. The binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
Subsequently, the functional distinction between alpha and beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources. As a result, alpha and beta adrenergic receptors were further subdivided into alpha 1, alpha 2, xcex21, and xcex22 subtypes. Functional differences between alpha 1 and alpha 2 receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed.
For a general background on the alpha adrenergic receptors, the reader""s attention is directed to Robert R. Ruffolo, Jr., xcex1-Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology, (Progress in Basic and Clinical Pharmacology series, Karger, 1991), wherein the basis of alpha 1/alpha 2 subclassification, the molecular biology, signal transduction (G-protein interaction and location of the significant site for this and ligand binding activity away from the 3xe2x80x2-terminus of alpha adrenergic receptors), agonist structure-activity relationships, receptor functions, and therapeutic applications for compounds exhibiting alpha-adrenergic receptor affinity was explored.
The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the alpha 1 receptors into alpha 1d (formerly known as alpha 1a or 1a/1d), alpha 1b and alpha 1a (formerly known as alpha 1c) subtypes. Each alpha 1 receptor subtype exhibits its own pharmacologic and tissue specificities. The designation xe2x80x9calpha 1axe2x80x9d is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated xe2x80x9calpha 1cxe2x80x9d cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). The designation alpha 1a is used throughout this application to refer to this subtype. At the same time, the receptor formerly designated alpha 1a was renamed alpha 1d. The new nomenclature is used throughout this application. Stable cell lines expressing these alpha 1 receptor subtypes are referred to herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature. For a review of the classification of alpha 1 adrenoceptor subtypes, see, Michel et al., Naunyn-Schmiedeberg""s Arch. Pharmacol. (1995), 352:1-10.
The differences in the alpha adrenergic receptor subtypes have relevance in pathophysiologic conditions. Benign prostatic hyperplasia, also known as benign prostatic hypertrophy or BPH, is an illness typically affecting men over fifty years of age, increasing in severity with increasing age. The symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra. Concommitantly, the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra.
In benign prostatic hyperplasia, the male hormone 5alpha-dihydrotestosterone has been identified as the principal culprit. The continual production of 5xcex1-dihydrotestosterone by the male testes induces incremental growth of the prostate gland throughout the life of the male. Beyond the age of about fifty years, in many men, this enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above.
The elucidation of the mechanism summarized above has resulted in the recent development of effective agents to control, and in many cases reverse, the pernicious advance of BPH. In the forefront of these agents is Merck and Co., Inc.""s product PROSCAR(copyright) (finasteride). The effect of this compound is to inhibit the enzyme testosterone 5-xcex1 reductase, which converts testosterone into 5xcex1-dihydrotesterone, resulting in a reduced rate of prostatic enlargement, and often reduction in prostatic mass.
The development of such agents as PROSCAR(copyright) bodes well for the long-term control of BPH. However, as may be appreciated from the lengthy development of the syndrome, its reversal also is not immediate. In the interim, those males suffering with BPH continue to suffer, and may in fact lose hope that the agents are working sufficiently rapidly.
In response to this problem, one solution is to identify pharmaceutically active compounds which complement slower-acting therapeutics by providing acute relief. Agents which induce relaxation of the lower urinary tract tissue, by binding to alpha 1 adrenergic receptors, thus reducing the increased adrenergic tone due to the disease, would be good candidates for this activity. Thus, one such agent is alfuzosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hyperplasia. Likewise, in WO 92/00073, the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the alpha 1 subtype was reported. In addition, in WO 92/16213, combinations of 5xcex1-reductase inhibitory compounds and alpha1-adrenergic receptor blockers (terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin) were disclosed. However, no information as to the alpha 1d, alpha 1b, or alpha 1a subtype specificity of these compounds was provided as this data and its relevancy to the treatment of BPH was not known. Current therapy for BPH uses existing non-selective alpha 1 antagonists such as prazosin (Minipress, Pfizer), Terazosin (Hytrin, Abbott) or doxazosin mesylate (Cardura, Pfizer). These non-selective antagonists suffer from side effects related to antagonism of the alpha 1d and alpha 1b receptors in the peripheral vasculature, e.g., hypotension and syncope.
The relatively recent cloning of the human alpha 1a adrenergic receptor (ATCC CRL 11140) and the use of a screening assay utilizing the cloned human alpha 1a receptor has enabled identification of compounds which specifically interact with the human alpha la adrenergic receptor. For further description, see WO 94/08040 and WO 94/10989. As disclosed in the instant patent disclosure, a cloned human alpha 1a adrenergic receptor and a method for identifying compounds which bind the human alpha 1a receptor have made possible the identification of selective human alpha 1a adrenergic receptor antagonists useful for treating BPH.
Several classes of compounds have been disclosed to be selective alpha 1a adrenergic receptor antagonists useful for treating BPH. WO 94/22829 discloses, for example, certain 4-(un)substituted phenyl-1,4-dihydropyridine derivatives which are described as potent, selective alpha 1a antagonists with weak calcium channel antagonistic activity and which are further described to be anticipated as useful for treating BPH. As another example, WO 96/14846, WO 97/17969 and WO 97/42956 each disclose certain dihydropyrimidine derivatives (e.g., certain 1,2,3,6-tetrahydro-2-oxo-pyrimidine derivatives) which are selective antagonists for the human alpha 1a receptor and useful for treatment of BPH, impotency, cardiac arrhythmia, and other diseases where antagonism of the alpha 1a receptor may be useful. As still another example, WO 96/40135 discloses, inter alia, certain phenylpiperidinyl alkyl saccharin derivatives and their use as selective alpha 1a antagonists. Other examples are U.S. Pat. No. 5,661,163 and WO 96/40136, which disclose, inter alia, piperidinyl- and piperazinyl-alkyl-substituted phenyl acetamides. Yet another example is EP 748800, which discloses, inter alia, certain arylpiperazinylpropyl substituted pyrimidinediones useful as alpha 1 adrenoceptor antagonists. Still other alpha 1a selective antagonist compounds are disclosed in WO 98/57632, WO 98/57638, WO 98/57639, WO 98/57640, WO 98/57641, WO 98/57642, and WO 98/57940.
The instant patent disclosure discloses novel spirotricyclic azacycloalkyl compounds (e.g., spirotricyclic azetidinyl, pyrrolidinyl, piperidinyl, etc. compounds) which bind to the human alpha 1a receptor. These compounds are further tested for binding to other human alpha 1 receptor subtypes, as well as counterscreened against other types of receptors (e.g., alpha 2), thus defining the specificity of the compounds of the present invention for the human alpha 1a adrenergic receptor.
It is an object of the present invention to identify compounds which bind to the alpha 1a adrenergic receptor. It is a further object of the invention to identify compounds which act as antagonists of the alpha 1a adrenergic receptor. It is another object of the invention to identify alpha 1a adrenergic receptor antagonist compounds which are useful agents for treating BPH in animals, preferably mammals, especially humans. Still another object of the invention is to identify alpha 1a adrenergic receptor antagonists which are useful for relaxing lower urinary tract tissue in animals, preferably mammals, especially humans.
The compounds of the present invention are alpha 1a adrenergic receptor antagonists. Thus, the compounds of the present invention are useful for treating BPH in mammals. Additionally, it has been found that the alpha 1a adrenergic receptor antagonists of the present invention are also useful for relaxing lower urinary tract tissue in mammals.
The present invention provides spirotricyclic azacycloalkyl compounds and pharmaceutically acceptable salts thereof for the treatment of urinary obstruction caused by benign prostatic hyperplasia (BPH). The compounds antagonize the human alpha 1a adrenergic receptor at nanomolar and subnanomolar concentrations while typically exhibiting lower affinity for the alpha 1d and alpha 1b human adrenergic receptors and many other G-protein coupled receptors. This invention can have the advantage over non-selective alpha 1 adrenoceptor antagonists of reduced side effects related to peripheral adrenergic blockade. Such side effects include hypotension, syncope, lethargy, etc.
More particularly, the present invention is a compound of formula (I): 
wherein Q is 
A1 is a benzene ring, substituted benzene, heterocyclic or substituted heterocyclic, wherein each of the substituents on substituted benzene or substituted heterocyclic is independently halogen, cyano, nitro, C1-C8 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C1-C6 alkoxy, fluorinated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalky;
A2 independently has the same definition as set forth for A1;
Z is absent, O, S, SO, SO2, NRa, Cxe2x95x90O, NRaC(xe2x95x90O), C(xe2x95x90O)NRa, NRaSO2, SO2NRa, C(RbRc), C(RbRc)C(RbRc), C(Rb)xe2x95x90C(Rc), C(RbRc)S, SC(RbRc), C(RbRc)SO, SOC(RbRc), C(RbRc)NRa, NRaC(RbRc), C(RbRc)C(xe2x95x90O), or C(xe2x95x90O)C(RbRc);
each Y is independently hydrogen, halogen, cyano, nitro, C1-C8 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C1-C6 alkoxy, fluorinated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
each X1 is independently hydrogen, halogen, cyano, nitro, C1-C8 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C1-C6 alkoxy, fluorinated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
each R1 is a substituent connected to a ring atom other than N or spiro subsituted carbon and is independently hydrogen or C1-C4 alkyl;
R2, R3, R4 and R5 are each independently selected from hydrogen, C1-C6 alkyl, and C3-C8 cycloalkyl;
R6 is hydrogen, C1-C8 alkyl, or fluorinated C1-C8 alkyl;
R7 and R8 are each independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C1-C6 alkoxy, CO2Rd, C2-C8 alkoxyalkyl, and fluorinated C2-C8 alkoxyalkyl;
R9 and R10 are each independently selected from hydrogen, C1-C6 alkyl, fluorinated C1-C6 alkyl, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, C4-C20 alkylcycloalkyl, C4-C20 cycloalkylalkyl, or CHReRf;
R12 and R14 are each independently selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, fluorinated C1-C6 alkyl, fluorinated C1-C6 alkoxy, fluorinated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, and fluorinated C2-C8 alkoxyalkyl; or one of R12 and R14 is CO2Rd or CON(Re)2 and the other of R12 and R14 is as earlier defined; or R12 and R14 together with the carbon atom to which they are attached form C3-C7 cycloalkyl or substituted C3-C7 cycloalkyl, wherein the each of the substituents on substituted cycloalkyl is independently halogen, cyano, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, CO2Rd, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
R16 and R18 are each independently selected from hydrogen, C1-C6 alkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heterocyclic, and substituted heterocyclic, provided that R16 and R18 are not both hydrogen; wherein each of the substituents on substituted phenyl or substituted naphthyl is independently halogen, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, CO2Rd, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl; and wherein each of the substituents on substituted heterocyclic is independently halogen, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, C2-C8 alkoxyalkyl, fluorinated C2-C8 alkoxyalkyl, or phenyl;
Ra is hydrogen, C1-C6 alkyl, fluorinated C1-C6 alkyl, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, C4-C20 alkylcycloalkyl, or C4-C20 cycloalkylalkyl;
Rb and Rc are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, fluorinated C1-C6 alkyl, phenyl, and substituted phenyl, wherein each of the substituents on the substituted phenyl is independently halo, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, CO2Rd, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
Rd is hydrogen, C1-C6 alkyl, fluorinated C1-C6 alkyl, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, C4-C20 alkylcycloalkyl, or C4-C20 cycloalkylalkyl;
Re is hydrogen or C1-C6 alkyl;
Rf is phenyl or substituted phenyl, wherein each of the substituents on substituted phenyl is halogen, cyano, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, or CO2Rd, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
m and n are each independently integers from 0 to 3;
p is an integer from 1 to 5;
q is 0 or 1, provided that when Q is 
then q is 0;
s is an integer from 0 to 4;
t1 is an integer from 0 to 4; and
t2 is an integer from 0 to 5;
or a pharmaceutically acceptable salt thereof.
The present invention also includes pharmaceutical compositions, methods of preparing pharmaceutical compositions, and methods of treatment.
These and other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples and appended claims.
The present invention includes spirotricyclic compounds of Formula (I) above. These compounds and their pharmaceutically acceptable salts are useful as alpha 1a antagonists.
A first embodiment of the present invention is a compound of Formula1a (I), wherein
A1 is a benzene ring, substituted benzene ring, heteroaryl, or substituted heteroaryl;
A2 independently has the same definition as set forth for A1;
Z is absent, O, S, SO, SO2, NRa, C(RbRc), C(RbRc)C(RbRc), or C(Rb)xe2x95x90C(Rc);
one of R2 and R3 is hydrogen and the other of R2 and R3 is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl;
one of R4 and R5 is hydrogen and the other of R4 and R5 is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl;
R16 and R18 are each independently selected from hydrogen, C1-C6 alkyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heterocyclic, and substituted heterocyclic, provided that R16 and R18 are not both hydrogen; wherein each heterocyclic is independently pyridyl, thienyl, or furanyl;
m and n are each integers from 0 to 3, provided that the sum of m and n is an integer less than or equal to 3;
and all other variables are as originally defined above;
or a pharmaceutically acceptable salt thereof.
A second embodiment of the present invention is a compound of formula (II): 
wherein
each X2 is independently hydrogen, halogen, cyano, C1-C8 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C1-C6 alkoxy, fluorinated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
w1 and w2 are each independently integers from 0 to 4;
and all other variables are as defined in the first embodiment;
or a pharmaceutically acceptable salt thereof.
A first class of the present invention is a compound of Formula (II), wherein Q is 
and all other variables are as defined in the second embodiment;
or a pharmaceutically acceptable salt thereof
A subclass of the preceding class is a compound of Formula (III): 
wherein
R7 and R8 are each independently selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, (CH2)0-4CF3, OCF3, CO2Rd, (CH2)1-4OCH3, and (CH2)1-4OCF3;
R9 is hydrogen, C1-C4 alkyl, (CH2)0-4CF3, C3-C6 cycloalkyl, or fluorinated C3-C6 cycloalkyl;
R12 and R14 are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, (CH2)0-4CF3, OCF3, fluorinated C3-C6 cycloalkyl, (CH2)1-4OCH3, (CH2)1-4OCF3; or one of R12 and R14 is CO2Rd or CON(Re)2 and the other of R12 and R14 is as earlier defined; or R12 and R14 together with the carbon atom to which they are attached form C3-C7 cycloalkyl;
one of R16 and R18 is hydrogen, C1-C4 alkyl, phenyl, mono- or di- or tri-substituted phenyl, naphthyl, mono- or di- or tri-substituted naphthyl, heterocyclic, or mono- or di- or tri-substituted heterocyclic; the other of R16 and R18 is phenyl, mono- or di- or tri-substituted phenyl, naphthyl, mono- or di- or tri-substituted naphthyl, heterocyclic, or mono- or di- or tri-substituted heterocyclic; wherein each of the substituents on substituted phenyl or substituted naphthyl or substituted heterocyclic is independently halogen, C1-C4 alkyl, (CH2)0-4CF3, C1-C4 alkoxy, OCF3, CO2Rd, (CH2)1-4OCH3, and (CH2)1-4OCF3;
Rd is hydrogen, C1-C4 alkyl, (CH2)0-4CF3, C3-C6 cycloalkyl, or fluorinated C3-C6 cycloalkyl;
Re is hydrogen or C1-C4 alkyl;
p is an integer from 2 to 5;
and all other variables are as defined in the first class;
or a pharmaceutically acceptable salt thereof.
Exemplary of compounds of the second embodiment of the present invention are compounds selected from the group consisting of
(+)-1xe2x80x2-{5-[((4(S)-(3,4-difluorophenyl)-2-oxo-oxazolidin)-3-yl)]-pentyl}-spirofluorene-9,4xe2x80x2-piperidine;
1xe2x80x2-[3-(5,5-bis-p-tolyl-2,4-dioxoimidazolidin-3-yl)propyl]spirofluorene-9,4xe2x80x2-piperidine;
1xe2x80x2-{6-[((4S)-(3,4-difluorophenyl)-2-oxooxazolidin)-3-yl]hexyl}-spirofluorene-9,4xe2x80x2-piperidine;
1xe2x80x2-{3-[(4S)-(3,4-difluorophenyl)-2-oxooxazolidin-3-carbonylamino]propyl}spirofluorene-9,4xe2x80x2-piperidine;
1xe2x80x2-{3-[(2S)-(3,4-difluorophenyl)-4-oxooxazolidin-3-carbonylamino]propyl}spirofluorene-9,4xe2x80x2-piperidine;
1,2,3,6-tetrahydro-1-[(spirofluorene-9,4xe2x80x2-piperidin-1xe2x80x2-yl)propyl]aminocarbonyl-5-methoxycarbonyl-4-methoxymethyl-6(S)-(3,4-difluorophenyl)-2-oxopyrimidine;
1xe2x80x2-[3-(5,5-bis-p-tolyl-2,4-dioxoimidazolidin-3-yl)propyl]-2-bromospirofluorene-9,4xe2x80x2-piperidine;
1,2,3,6-tetrahydro-1-[((2-bromospirofluorene-9,4xe2x80x2-piperidin)-1xe2x80x2-yl)propyl]aminocarbonyl-5-methoxycarbonyl-4-methoxymethyl-6(S)-(3,4-difluorophenyl)-2-oxopyrimidine;
1xe2x80x2-{3-[(4S)-(3,4-difluorophenyl)-2-oxooxazolidin-3-carbonylamino]propyl}-(2-bromospirofluorene-9,4xe2x80x2-piperidine);
1,2,3,6-tetrahydro-1-[((2-fluorospirofluorene-9,4xe2x80x2-piperidin)-1xe2x80x2-yl)propyl]aminocarbonyl-5-methoxycarbonyl-4-methoxymethyl-6(S)-(3,4-difluorophenyl)-2-oxopyrimidine;
1xe2x80x2-{3-[(4S)-(3,4-difluorophenyl)-2-oxooxazolidin-3-carbonylamino]propyl}-(2-fluorospirofluorene-9,4xe2x80x2-piperidine);
and pharmaceutically acceptable salts thereof.
A third embodiment of the present invention is a compound of Formula (IV): 
wherein
Z is O, S, SO, or SO2;
each X2 is independently hydrogen, halogen, cyano, C1-C8 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C1-C6 alkoxy, fluorinated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
w1 and w2 are each independently integers from 0 to 4;
and all other variables are as defined in the first embodiment;
or a pharmaceutically acceptable salt thereof.
A second class of the invention is a compound of Formula (IV), wherein Q is 
and all other variables are as defined in the third embodiment;
or a pharmaceutically acceptable salt thereof.
A subclass of the preceding class is a compound of Formula (V): 
wherein
R7 and R8 are each independently selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, (CH2)0-4CF3, OCF3, CO2Rd, (CH2)1-4OCH3, and (CH2)1-4OCF3;
R9 is hydrogen, C1-C4 alkyl, (CH2)0-4CF3, C3-C6 cycloalkyl, or fluorinated C3-C6 cycloalkyl;
R12 and R14 are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, (CH2)0-4CF3, OCF3, fluorinated C3-C6 cycloalkyl, (CH2)1-4OCH3, (CH2)1-4OCF3; or one of R12 and R14 is CO2Rd or CON(Re)2 and the other of R12 and R14 is as earlier defined; or R12 and R14 together with the carbon atom to which they are attached form C3-C7 cycloalkyl;
one of R16 and R18 is hydrogen, C1-C4 alkyl, phenyl, mono- or di- or tri-substituted phenyl, naphthyl, mono- or di- or tri-substituted naphthyl, heterocyclic, or mono- or di- or tri-substituted heterocyclic; the other of R16 and R18 is phenyl, mono- or di- or tri-substituted phenyl, naphthyl, mono- or di- or tri-substituted naphthyl, heterocyclic, or mono- or di- or tri-substituted heterocyclic; wherein each of the substituents on substituted phenyl or substituted naphthyl or substituted heterocyclic is independently halogen, C1-C4 alkyl, (CH2)0-4CF3, C1-C4 alkoxy, OCF3, CO2Rd, (CH2)1-4OCH3, and (CH2)1-4OCF3;
Rd is hydrogen, C1-C4 alkyl, (CH2)0-4CF3, C3-C6 cycloalkyl, or fluorinated C3-C6 cycloalkyl;
Re is hydrogen or C1-C4 alkyl;
p is an integer from 2 to 5;
and all other variables are as defined in the second class;
or a pharmaceutically acceptable salt thereof.
Exemplary of compounds of the third embodiment of the present invention are compounds selected from the group consisting of
4-(S)-(+)-(3,4-difluorophenyl)-3-[4-(spirothioxanthen-9,4xe2x80x2-piperidin-1xe2x80x2-yl)-butyl]-oxazolidin-2-one;
4-(S)-(3,4-difluorophenyl)-3-[5-(spirothioxanthen-9,4xe2x80x2-piperidin-1xe2x80x2-yl)-pentyl]-oxazolidin-2-one;
4-(S)-(3,4-difluorophenyl)-3-[6-(spirothioxanthen-9,4xe2x80x2-piperidin-1xe2x80x2-yl)-hexyl]-oxazolidin-2-one;
1xe2x80x2-{3-[(4S)-(3,4-difluorophenyl)-2-oxooxazolidin-3-carbonylamino]propyl}-(spirothioxanthene-9,4xe2x80x2-piperidine);
1,2,3,6-tetrahydro-1-[(spirothioxanthene-9,4xe2x80x2-piperidin-1xe2x80x2-yl)propyl]aminocarbonyl-5-methoxycarbonyl-4-methoxymethyl-6(S)-(3,4-difluorophenyl)-2-oxopyrimidine;
1xe2x80x2-{3-[(4S)-(3,4-difluorophenyl)-2-oxooxazolidin-3-carbonylamino]propyl}-(10-oxo-spirothioxanthene-9,4xe2x80x2-piperidine);
1,2,3,6-tetrahydro-1-[(10-oxo-spirothioxanthene-9,4xe2x80x2-piperidin-1xe2x80x2-yl)propyl]aminocarbonyl-5-methoxycarbonyl-4-methoxymethyl-6(S)-(3,4-difluorophenyl)-2-oxopyrimidine;
1xe2x80x2-{3-[(4S)-(3,4-difluorophenyl)-2-oxooxazolidin-3-carbonylamino]propyl}-(10,10-dioxo-spirothioxanthene-9,4xe2x80x2-piperidine);
1,2,3,6-tetrahydro-1-[(10,10-dioxo-spirothioxanthene-9,4xe2x80x2-piperidin-1xe2x80x2-yl)propyl]aminocarbonyl-5-methoxycarbonyl-4-methoxymethyl-6(S)-(3,4-difluorophenyl)-2-oxopyrimidine;
1xe2x80x2-{3-[(4S)-(3,4-difluorophenyl)-2-oxooxazolidin-3-carbonylamino]propyl}spiroxanthene-9,4xe2x80x2-piperidine;
1,2,3,6-tetrahydro-1-[(spiroxanthene-9,4xe2x80x2-piperidin-1xe2x80x2-yl)propyl]aminocarbonyl-5-methoxycarbonyl-4-methoxymethyl-6(S)-(3,4-difluorophenyl)-2-oxopyrimidine;
1xe2x80x2-[3-(5,5-bis-p-tolyl-2,4-dioxoimidazolidin-3-yl)propyl]spiroxanthene-9,4xe2x80x2-piperidine;
1xe2x80x2-[3-(5,5-bis-p-tolyl-2,4-dioxoimidazolidin-3-yl)propyl]-2-chlorospiroxanthene-9,4xe2x80x2-piperidine;
1xe2x80x2-{3-[(4S)-(3,4-difluorophenyl)-2-oxooxazolidin-3-carbonylamino]propyl}-2-chlorospiroxanthene-9,4xe2x80x2-piperidine;
1,2,3,6-tetrahydro-1-[((2-chlorospiroxanthene-9,4xe2x80x2-piperidin)-1xe2x80x2-yl)propyl]aminocarbonyl-5-methoxycarbonyl-4-methoxymethyl-6(S)-(3,4-difluorophenyl)-2-oxopyrimidine;
1xe2x80x2-{3-[(4S)-(3,4-difluorophenyl)-2-oxooxazolidin-3-carbonylamino]propyl}-2,7-dichlorospiroxanthene-9,4xe2x80x2-piperidine;
1xe2x80x2-{3-[(4S)-(3,4-difluorophenyl)-2-oxooxazolidin-3-carbonylamino]propyl}-2,7-difluorospiroxanthene-9,4xe2x80x2-piperidine;
and pharmaceutically acceptable salts thereof.
A fourth embodiment of the present invention is a compound of Formula (VI): 
wherein one of A1 and A2 is a benzene ring, substituted benzene ring, 6-membered heteroaryl, or substituted 6-membered heteroaryl; and the other of A1 and A2 is 6-membered heteroaryl or substituted 6-membered heteroaryl; wherein each heteroaryl ring has 1 or 2 nitrogen atoms and a balance of carbon atoms;
and all other variables are as defined in the first embodiment;
or a pharmaceutically acceptable salt thereof.
A third class of the present invention is a compound of Formula (VI), wherein Q is 
and all other variables are as defined in the fourth embodiment;
or a pharmaceutically acceptable salt thereof.
A subclass of the preceding class is a compound of Formula (VII) 
wherein
K and L are each independently CX2 or N, provided that at least one value K or L is N;
each X2 is independently hydrogen, halogen, cyano, C1-C8 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C1-C6 alkoxy, fluorinated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
R7 and R8 are each independently selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, (CH2)0-4CF3, OCF3, CO2Rd, (CH2)1-4OCH3, and (CH2)1-4OCF3;
R9 is hydrogen, C1-C4 alkyl, (CH2)0-4CF3, C3-C6 cycloalkyl, or fluorinated C3-C6 cycloalkyl;
R12 and R14 are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, (CH2)0-4CF3, OCF3, fluorinated C3-C6 cycloalkyl, (CH2)1-4OCH3, (CH2)1-4OCF3; or one of R12 and R14 is CO2Rd or CON(Re)2 and the other of R12 and R14 is as earlier defined; or R12 and R14 together with the carbon atom to which they are attached form C3-C7 cycloalkyl;
one of R16 and R18 is hydrogen, C1-C4 alkyl, phenyl, mono- or di- or tri-substituted phenyl, naphthyl, mono- or di- or tri-substituted naphthyl, heterocyclic, or mono- or di- or tri-substituted heterocyclic; the other of R16 and R18 is phenyl, mono- or di- or tri-substituted phenyl, naphthyl, mono- or di- or tri-substituted naphthyl, heterocyclic, or mono- or di- or tri-substituted heterocyclic; wherein each of the substituents on substituted phenyl or substituted naphthyl or substituted heterocyclic is independently halogen, C1-C4 alkyl, (CH2)0-4CF3, C1-C4 alkoxy, OCF3, CO2Rd, (CH2)1-4OCH3, and (CH2)1-4OCF3;
Rd is hydrogen, C1-C4 alkyl, (CH2)0-4CF3, C3-C6 cycloalkyl, or fluorinated C3-C6 cycloalkyl;
Re is hydrogen or C1-C4 alkyl;
p is an integer from 2 to 5;
and all other variables are as defined in the third class;
or a pharmaceutically acceptable salt thereof.
Exemplary of compounds of the fourth embodiment are compounds selected from the group consisting of
1xe2x80x2-{5-[(4(S)-(3,4-difluorophenyl)-2-oxooxazolidin)-3-yl]-pentyl}-(spiro-5H-indeno[1,2-b]pyridine)-5,4xe2x80x2-piperidine;
1xe2x80x2-{3-[(4S)-(3,4-difluorophenyl)-2-oxooxazolidin-3-carbonylamino]propyl}-(spiro-5H-indeno[1,2-b]pyridine)-5,4xe2x80x2-piperidine;
1,2,3,6-tetrahydro-1-[3-(spiro(5H-indeno[1,2-b]pyridine)-5,4xe2x80x2-piperidin)-1xe2x80x2-yl)propylaminocarbonyl]-5-methoxycarbonyl-4-methoxymethyl-6(S)-(3,4-difluorophenyl)-2-oxopyrimidine;
1xe2x80x2-{3-[(4S)-(3,4-difluorophenyl)-2-oxooxazolidin-3-carbonylamino]propyl}-(spiro-9H-indeno[2,1-b]pyridine)-9,4xe2x80x2-piperidine;
1,2,3,6-tetrahydro-1-[3-((spiro(9H-indeno[2,1-b]pyridine)-9,4xe2x80x2-piperidin)-1xe2x80x2-yl)propylaminocarbonyl]-5-methoxycarbonyl-4-methoxymethyl-6(S)-(3,4-difluorophenyl)-2-oxopyrimidine;
and pharmaceutically acceptable salts thereof.
A fifth embodiment of the present invention is a compound of Formula (VIII): 
wherein
Z is C(RbRc) or C(RbRc)C(RbRc);
each X2 is independently hydrogen, halogen, cyano, C1-C8 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C1-C6 alkoxy, fluorinated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl;
w1 and w2 are each independently integers from 0 to 4;
and all other variables are as defined in the first embodiment;
or a pharmaceutically acceptable salt thereof.
A fourth class of the invention is a compound of Formula (VIII), wherein Q is 
and all other variables are as defined in the fifth embodiment;
or a pharmaceutically acceptable salt thereof.
A subclass of the preceding class is a compound of Formula (IX): 
wherein
Z is C(HRb), C(HRb)C(HRc), or C(Rb)xe2x95x90C(Rc);
R7 and R8 are each independently selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, (CH2)0-4CF3, OCF3, CO2Rd, (CH2)1-4OCH3, and (CH2)1-4OCF3;
R9 is hydrogen, C1-C4 alkyl, (CH2)0-4CF3, C3-C6 cycloalkyl, or fluorinated C3-C6 cycloalkyl;
R12 and R14 are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, (CH2)0-4CF3, OCF3, fluorinated C3-C6 cycloalkyl, (CH2)1-4OCH3, (CH2)1-4OCF3; or one of R12 and R14 is CO2Rd or CON(Re)2 and the other of R12 and R14 is as earlier defined; or R12 and R14 together with the carbon atom to which they are attached form C3-C7 cycloalkyl;
one of R16 and R18 is hydrogen, C1-C4 alkyl, phenyl, mono- or di- or tri-substituted phenyl, naphthyl, mono- or di- or tri-substituted naphthyl, heterocyclic, or mono- or di- or tri-substituted heterocyclic; the other of R16 and R18 is phenyl, mono- or di- or tri-substituted phenyl, naphthyl, mono- or di- or tri-substituted naphthyl, heterocyclic, or mono- or di- or tri-substituted heterocyclic; wherein each of the substituents on substituted phenyl or substituted naphthyl or substituted heterocyclic is independently halogen, C1-C4 alkyl, (CH2)0-4CF3, C1-C4 alkoxy, OCF3, CO2Rd, (CH2)1-4OCH3, and (CH2)1-4OCF3;
each Rb and each Rc is independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, (CH2)0-4CF3, phenyl, or substituted phenyl, wherein each of the substituents on substituted phenyl is independently halogen, C1-C4 alkyl, (CH2)0-4CF3, C1-C4 alkoxy, OCF3, CO2Rd, (CH2)0-4OCH3, or (CH2)0-4OCF3;
Rd is hydrogen, C1-C4 alkyl, (CH2)0-4CF3, C3-C6 cycloalkyl, or fluorinated C3-C6 cycloalkyl;
Re is hydrogen or C1-C4 alkyl;
p is an integer from 2 to 5;
and all other variables are as defined in the fourth class;
or a pharmaceutically acceptable salt thereof.
Exemplary compounds of the fifth embodiment are compounds selected from the group consisting of
1,2,3,6-tetrahydro-1-[3-((10,11-dihydrospiro-5H-dibenzo[a,d] cycloheptene-5,4xe2x80x2-piperidin)-1xe2x80x2-yl)propylaminocarbonyl]-5-methoxycarbonyl-4-methoxymethyl-6(S)-(3,4-difluorophenyl)-2-oxopyrimidine;
1xe2x80x2-{3-[4(S)-(3,4-difluorophenyl)-2-oxooxazolidin-3-carbonylamino]-propyl}-(10,11-dihydrospiro-5H-dibenzo[a,d] cycloheptene)-5,4xe2x80x2-piperidine;
1xe2x80x2-{5-[4(S)-(3,4-difluorophenyl)-2-oxooxazolidin-3-yl]-pentyl}-(10,11-dihydrospiro-5H-dibenzo[a,d] cycloheptene)-5,4xe2x80x2-piperidine;
and pharmaceutically acceptable salts thereof.
A preferred aspect of the present invention is 1,2,3,6-tetrahydro-1-[3-((spiro(9H-indeno[2,1-b]pyridine)-9,4xe2x80x2-piperidin)-1xe2x80x2-yl)-propylaminocarbonyl]-5-methoxycarbonyl-4-methoxymethyl-6(S)-(3,4-difluorophenyl)-2-oxopyrimidine (Example 53 below), or a pharmaceutically acceptable salt thereof.
The present invention also includes a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier. In one embodiment is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. The present invention further includes a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
The present invention further includes a pharmaceutical composition as described in the preceding paragraph further comprising a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor. In one embodiment, the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising any of the compounds described above combined with both a type 1 testosterone 5-alpha reductase inhibitor and a type 2 testosterone 5-alpha reductase inhibitor), or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor. In another embodiment, the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor. The testosterone 5-alpha reductase inhibitor is suitably finasteride.
The present invention also includes a method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above. In one embodiment of the method of treating BPH, the compound (or composition) does not cause a fall in blood pressure at dosages effective to alleviate BPH. In another embodiment of the method of treating BPH, the compound is administered in combination with a testosterone 5-alpha reductase inhibitor. A suitable testosterone 5-alpha reductase inhibitor for use in the method is finasteride.
The present invention also includes a method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above. In one embodiment of the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue, the compound (or composition) additionally does not cause a fall in blood pressure at dosages effective to inhibit contraction of prostate tissue. In another embodiment, the compound is administered in combination with a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor; the testosterone 5-alpha reductase inhibitor is suitably finasteride.
The present invention also includes a method of treating a disease which is susceptible to treatment by antagonism of the alpha 1a receptor which comprises administering to a subject in need thereof an amount of any of the compounds described above effective to treat the disease. Diseases which are susceptible to treatment by antagonism of the alpha 1a receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, impotency, sympathetically mediated pain, migraine (see Vatz, Headache (1997), 37: 107-108) and cardiac arrhythmia.
The present invention also includes a method of preventing or treating prostatic cancer which comprises administering to a subject in need of prevention or treatment thereof a therapeutically effective amount of a combination comprising any of the compounds (or compositions) described above and a testosterone 5-alpha-reductase inhibitor. The testosterone 5-alpha reductase inhibitor is suitably finasteride.
The present invention also includes the use of any of the compounds described above in the preparation of a medicament for: a) treating benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue; in a subject in need thereof.
The present invention further includes the use of any of the alpha 1a antagonist compounds described above and a 5-alpha reductase inhibitor for the manufacture of a medicament for: a) treating benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue which comprises an effective amount of the alpha 1a antagonist compound and an effective amount of 5-alpha reductase inhibitor, together or separately.
As used herein, the term xe2x80x9cC1-C8 alkylxe2x80x9d means linear or branched chain alkyl groups having from 1 to 8 carbon atoms and includes all of the octyl alkyl, heptyl alkyl, hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. xe2x80x9cC1-C6 alkylxe2x80x9d means linear or branched chain alkyl groups having from 1 to 6 carbon atoms and includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. xe2x80x9cC1-C4 alkylxe2x80x9d means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
The term xe2x80x9cC1-C6 alkoxyxe2x80x9d means an xe2x80x94Oxe2x80x94alkyl group wherein alkyl is C1-C6 alkyl, as defined above. xe2x80x9cC1-C4 alkoxyxe2x80x9d has an analogous meaning; i.e., it is an alkoxy group selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and sec-butoxy.
The term xe2x80x9cC2-C8 alkoxyalkylxe2x80x9d means a linear or branched C1-C6 alkyl group as defined above having as a substituent a C1-C6 alkoxy group as defined above, wherein the alkoxyalkyl group has a total of from 2 to 8 carbon atoms. Representative examples of suitable alkoxyalkyl groups include, but are not limited to, the C1-C6 alkoxy-substituted methyl groups (methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, and the butyloxymethyl, pentyloxymethyl, and hexyloxymethyl isomers), and the C1-C6 alkoxy-substituted ethyl groups. Other suitable alkoxyalkyl groups include the series (CH2)1-6OCH3, (CH2)1-4OCH3, (CH2)1-6OCH2CH3, and (CH2)1-4OCH2CH3.
The term xe2x80x9cC3-C8 cycloalkylxe2x80x9d means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl). xe2x80x9cC3-C7 cycloalkylxe2x80x9d refers to a cyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. xe2x80x9cC3-C6 cycloalkylxe2x80x9d refers to a cyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term xe2x80x9cC4-C20 alkylcycloalkylxe2x80x9d means a C3-C8 cycloalkyl as defined above substituted with one or more C1-C8 alkyl groups as defined above, wherein the total number of carbon atoms in the alkylcycloalkyl group is in the range of from 4 to 20. xe2x80x9cC6-C14 alkylcycloalkylxe2x80x9d means a C3-C6 cycloalkyl as defined above substituted with one or more C1-C4 alkyl groups as defined above, wherein the total number of carbon atoms in the alkylcycloalkyl group is in the range of from 6 to 14. Representative examples include methylcyclohexyl (i.e., 2-, 3- and 4-methylcyclohexyl), ethylcyclohexyl, methylcyclopentyl, dimethylcyclohexyl (i.e., 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dimethylcyclohexyl), methylcyclobutyl, and so forth.
The term xe2x80x9cC4-C20 cycloalkylalkylxe2x80x9d means a C1-C8 alkyl group as defined above substituted with one or more C3-C8 cycloalkyls as defined above, wherein the total number of carbon atoms in the cycloalkyl alkyl group is in the range of from 4 to 20. xe2x80x9cC6-C14 cycloalkyl-alkylxe2x80x9d means a C1-C4 alkyl group as defined above substituted with one or more C3-C6 cycloalkyl groups as defined above, wherein the total number of carbon atoms in the alkylcycloalkyl group is in the range of from 5 to 14. Representative examples include cyclohexylmethyl, 1- and 2-cyclohexylethyl, cyclohexylisopropyl, 1- and 3-cyclohexyl-n-propyl, dicyclohexylmethyl, and so forth.
The term xe2x80x9chalogenxe2x80x9d (which may alternatively be referred to as xe2x80x9chaloxe2x80x9d) refers to fluorine, chlorine, bromine and iodine (alternatively, fluoro, chloro, bromo, and iodo).
The term xe2x80x9cfluorinated C1-C8 alkylxe2x80x9d (which may alternatively be referred to as xe2x80x9cC1-C8 fluoroalkylxe2x80x9d) means a C1 to C8 linear or branched alkyl group as defined above with one or more fluorine substituents. The terms xe2x80x9cfluorinated C1-C4 alkylxe2x80x9d and xe2x80x9cfluorinated C1-C6 alkylxe2x80x9d have analogous meanings. Representative examples of suitable fluoroalkyls include the series (CH2)0-4CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.), 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 3,3,3-trifluoroisopropyl, 1,1,1,3,3,3-hexafluoroisopropyl, and perfluorohexyl.
The term xe2x80x9cfluorinated C3-C8 cycloalkylxe2x80x9d (which may alternatively be referred to as xe2x80x9cC3-C8 fluorocycloalkylxe2x80x9d) means a cycloalkyl group as defined above with one or more fluorine substituents. The terms xe2x80x9cfluorinated C3-C7 cycloalkylxe2x80x9d and xe2x80x9cfluorinated C3-C6 cycloalkylxe2x80x9d have analogous meanings. Representative examples of suitable fluorocycloalkyls include all isomers of fluorocyclohexyl (i.e., 1-, 2-, 3-, and 4-fluorocyclohexyl), difluorocyclohexyl (e.g., 2,4-difluorocyclohexyl, 3,4-difluorocyclohexyl, etc.), fluorocyclopentyl, and so forth.
The term xe2x80x9cfluorinated C1-C6 alkoxyxe2x80x9d (which may alternatively be referred to as xe2x80x9cC1-C6 fluoroalkylxe2x80x9d) means a C1-C6 alkoxy group as defined above wherein the alkyl moiety has one or more fluorine substituents. The term xe2x80x9cfluorinated C1-C4 alkoxyxe2x80x9d has an analogous meaning. Representative examples include the series O(CH2)0-4CF3 (i.e., trifluoromethoxy, 2,2,2-trifluoroethoxy, 3,3,3-trifluoro-n-propoxy, etc.), 1,1,1,3,3,3-hexafluoroisopropoxy, and so forth.
The term xe2x80x9cfluorinated C2-C8 alkoxyalkylxe2x80x9d means C2-C8 alkoxyalkyl as defined above, wherein either or both the alkoxy moiety and the alkyl moiety has one or more fluorine substituents. Representative examples of suitable fluorinated alkoxyalkyl groups include, but are not limited to, the C1-C6 fluoroalkoxy-substituted methyl groups (e.g., fluoromethoxymethyl, 2-fluoroethoxymethyl, and 3-fluoro-n-propoxymethyl), C1-C6 difluoroalkoxymethyl groups (e.g., difluoromethoxymethyl and 2,2-difluoroethoxymethyl), C1-C6 trifluoroalkoxy-substituted methyl groups (e.g., trifluoromethoxymethyl and 2,2,2-trifluoroethoxymethyl), C1-C6 alkoxy-substituted fluoromethyl groups (e.g., methoxy- or ethoxy-fluoromethyl), and C1-C6 alkoxy-substituted difluoromethyl groups (e.g., methoxy- or ethoxy-difluoromethyl). Other suitable fluorinated alkoxyalkyl groups include the series (CH2)1-6OCF3, (CH2)1-4OCF3, (CH2)1-6OCH2CF3, and (CH2)1-4OCH2CF3.
The term xe2x80x9cheterocyclicxe2x80x9d (which may alternatively be referred to as xe2x80x9cheterocyclexe2x80x9d) refers to a stable 5- to 7-membered monocyclic ring system which may be saturated or unsaturated; which consists of carbon atoms and from one to three heteroatoms selected from N, O or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring may be attached at any single heteroatom or carbon atom, or with respect to the definitions of A1 and A2 may be fused to another ring system by two adjacent ring carbon atoms, provided that attachment or fusion results in the creation of a stable structure. Suitable heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl, and triazolyl. Morpholino is the same as morpholinyl.
The term xe2x80x9cthienyl,xe2x80x9d as used herein, refers to the group 
xe2x80x9cFused thienylxe2x80x9d refers to 
The term xe2x80x9csubstituted heterocyclicxe2x80x9d refers to a heterocyclic group as defined above having one or more subsituents independently selected from halogen, cyano, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, C2-C8 alkoxyalkyl, fluorinated C2-C8 alkoxyalkyl, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, amino, Nxe2x80x94(C1-C6 alkyl)amino, N,N-di-(C1-C6 alkyl)amino, aryl (defined below), carboxy, C1-C6 alkoxycarbonyl, sulfonamido, sulfonyl, and the like.
The term xe2x80x9carylxe2x80x9d refers herein to aromatic mono- and poly-carbocyclic ring systems, wherein the carbocyclic rings in the polyring systems may be fused or attached via a single ring carbon. Suitable aryl groups include, but are not limited to, phenyl, naphthyl, and biphenylenyl.
xe2x80x9cSubstituted arylxe2x80x9d refers to aryl groups as defined above having one or more substituents independently selected from halogen, cyano, C1-C6 alkyl, fluorinated C1-C6 alkyl, C1-C6 alkoxy, fluorinated C1-C6 alkoxy, C2-C8 alkoxyalkyl, fluorinated C2-C8 alkoxyalkyl, C3-C8 cycloalkyl, fluorinated C3-C8 cycloalkyl, amino, N-C1-C6 alkylamino, N,N-di-(C1-C6)alkylamino, aryl, carboxy, C1-C6 alkoxycarbonyl, sulfonamido, sulfonyl, and the like.
The term xe2x80x9cheteroarylxe2x80x9d refers to the subset of heterocycles as heretofore defined which are aromatic heterocyclic ring systems, including, but not limited to, pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl, oxazolyl, thiazolyl, and thiadiazolyl.
xe2x80x9cSubstituted heteroarylxe2x80x9d refers to heteroaryl groups as defined above having one or more substituents as defined above.
The term xe2x80x9csubstitutedxe2x80x9d includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution is chemically allowed.
The expression xe2x80x9cZ is absentxe2x80x9d means that Z is replaced by a bond; i.e., ring A1 in Formula (I) is fused to a cyclopentyl moiety.
It is understood that the definition of a substituent (e.g., CO2Rd) or variable (e.g., Rd) at a particular location in a molecule is independent of its definitions at other locations in that molecule. Thus, for example, when R7 is CO2Rdxe2x95x90CO2H, and R8 is CO2Rd, it is understood that R8 can be any one of CO2H, CO2Me, CO2Et, CO2Pr, etc. As another example, the moiety 
wherein R1 is hydrogen or C1-C4 alkyl, m=1, n=1, and s=2, represents moieties such as 
It is also understood that the definition of a substituent or variable at a particular location in a molecule is dependent of the definition of another occurrence of the same substituent or variable at the same location. Thus, C(xe2x95x90O)N(Re)2 represents groups such as xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NHCH3, xe2x80x94C(xe2x95x90O)NHC2H5, xe2x80x94C(xe2x95x90O)N(CH3)C2H5, etc.
It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the aft to provide compounds that are chemically stable and that can be readily synthesized by the methods set forth below and, when viewed in the light of this disclosure, by techniques known in the art. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.
Representative embodiments for the variables and substituents set forth in Formula (I) include the following:
A1 is a benzene ring (i.e., benzo), substituted benzene ring (i.e., substituted benzo), heteroaryl, or substituted heteroaryl, wherein the heteroaryl has from 1 to 2 heteroatoms selected from N, O and S; or A1 is benzo or mono- or di- or tri-substituted benzo, wherein each of the substituents on substituted benzo is independently halogen, cyano, C1-C8 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C1-C6 alkoxy, fluorinated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl; or A1 is heteroaryl or substituted heteroaryl, wherein the heteroaryl has 1 to 2 N atoms and the remaining atoms in the heteroaryl ring are carbon atoms, and each of the substituents on substituted heteroaryl is as previously set forth in this paragraph for substituted benzo; or A1 is 6-membered heteroaryl or substituted 6-membered heteroaryl, wherein each of the substituents on substituted heteroaryl is as set forth earlier in this paragraph for substituted benzo.
A2 independently has the same definition as set forth for A1. In one embodiment, one of A1 and A2 is benzo or substituted benzo, and the other of A1 and A2 is heteroaryl or substituted heteroaryl. In another embodiment, each of A1 and A2 is independently benzo or substituted benzo. In an aspect of the preceding embodiment, A1 is 
and A2 is 
wherein each X2 is independently hydrogen, halogen, cyano, C1-C8 alkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, fluorinated C1-C8 alkyl, fluorinated C1-C6 alkoxy, fluorinated C3-C8 cycloalkyl, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl; and w1 and w2 are each independently integers from 0 to 4. In one aspect of this embodiment, each X2 is independently hydrogen, halogen, C1-C4 alkyl, (CH2)0-4CF3, C1-C4 alkoxy, OCF3, CO2Rd, (CH2)1-4OCH3, or (CH2)1-4CF3. In other aspects, w1 and w2 are each independently integers from 0 to 3; or from 0 to 2.
Z is absent, O, S, SO, SO2, NRa, C(RbRc), C(RbRc)C(RbRc), or C(Rb)xe2x95x90C(Rc); or is absent, O, S, SO, SO2, NRa, C(RbRc), or C(RbRc)C(RbRc); or is absent, O, S, SO, SO2, CH2, or CH2CH2.
Each of X1 and Y is independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C4 alkoxy, C3-C7 cycloalkyl, fluorinated C1-C6 alkyl, fluorinated C1-C4 alkoxy, fluorinated C3-C7 cycloalkyl, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl; or is independently hydrogen, fluorine, chlorine, cyano, C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C1-C6 alkyl, fluorinated C3-C6 cycloalkyl, (CH2)0-4OCH3, or (CH2)0-4OCF3; or is hydrogen, fluorine, chlorine, cyano, methyl, ethyl, OCF3, CH2CF3, (CH2)0-2OCH3, and (CH2)0-2OCF3; or is hydrogen, fluorine, chlorine, cyano, methyl, ethyl, CF3, CH2CF3, (CH2)1-2OCH3, and (CH2)1-2OCF3.
each R1 is a substituent connected to a ring atom other than the spiro subsituted carbon or the N and is independently hydrogen, methyl or ethyl.
R2, R3, R4 and R5 are each independently selected from hydrogen and C1-C6 alkyl. In one embodiment, one of R2 and R3 is hydrogen and the other of R2 and R3 is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl; and one of R4 and R5 is hydrogen and the other of R4 and R5 is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl. In another embodiment, R2, R3, R4 and R5 are all hydrogen.
R6 is hydrogen, C1-C4 alkyl, or fluorinated C1-C4 alkyl; or is hydrogen.
R7 and R8 are each independently selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, (CH2)0-4CF3, OCF3, CO2Rd, (CH2)1-4OCH3, and (CH2)1-4OCF3.
R9 and R10 are each independently hydrogen, C1-C4 alkyl, (CH2)0-4CF3, C3-C6 cycloalkyl, or fluorinated C3-C6 cycloalkyl.
R12 and R14 are each independently selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, (CH2)0-4CF3, OCF3, fluorinated C3-C6 cycloalkyl, (CH2)1-4OCH3,(CH2)1-4OCF3; or one of R12 and R14 is CO2Rd or CON(Re)2 and the other of R12 and R14 is as earlier defined; or R12 and R14 together with the carbon atom to which they are attached form C3-C7 cycloalkyl.
One of R16 and R18 is hydrogen, C1-C4 alkyl, phenyl, mono-or di- or tri-substituted phenyl, naphthyl, mono- or di- or tri-substituted naphthyl, heterocyclic, or mono- or di- or tri-substituted heterocyclic; the other of R16 and R18 is phenyl, mono- or di- or tri-substituted phenyl, naphthyl, mono- or di- or tri-substituted naphthyl, heterocyclic, or mono- or di- or tri-substituted heterocyclic; wherein each of the substituents on substituted phenyl or substituted naphthyl or substituted heterocyclic is independently halogen, C1-C4 alkyl, (CH2)0-4CF3, C1-C4 alkoxy, OCF3, CO2Rd, (CH2)1-4OCH3, or (CH2)1-4OCF3.
Ra is hydrogen, C1-C4 alkyl, fluorinated C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C3-C6 cycloalkyl, C6-C14 alkylcycloalkyl, or C6-C14 cycloalkylalkyl; or is hydrogen, C1-C4 alkyl, or (CH2)0-4CF3; or is hydrogen, methyl, ethyl, or CF3; or is hydrogen.
One of Rb and Rc is hydrogen, and the other of Rb and Rc is hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, fluorinated C1-C4 alkyl, phenyl, or substituted phenyl, wherein each of the substituents on the substituted phenyl is independently halogen, C1-C4 alkyl, fluorinated C1-C4 alkyl, C1-C4 alkoxy, fluorinated C1-C4 alkoxy, CO2Rd, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl. In another embodiment, Rb and Rc are both hydrogen.
Rd is hydrogen, C1-C4 alkyl, (CH2)0-4CF3, C3-C6 cycloalkyl, or fluorinated C3-C6 cycloalkyl; or is hydrogen, methyl, ethyl, or (CH2)0-2CF3.
Re is hydrogen or C1-C4 alkyl; or is hydrogen, methyl, or ethyl; or is hydrogen.
Rf is phenyl or substituted phenyl, wherein each of the substituents on substituted phenyl is halogen, cyano, C1-C4 alkyl, fluorinated C1-C4 alkyl, C1-C4 alkoxy, fluorinated C1-C4 alkoxy, CO2Rd, C2-C8 alkoxyalkyl, or fluorinated C2-C8 alkoxyalkyl.
m and n are each integers from 0 to 3, provided that the sum of m and n is an integer less than or equal to 3. In another embodiment m and n are each independently integers from 0 to 1. In still another embodiment m and n are both 1.
p is an integer from 2 to 5; or from 2 to 4; or is 2; or is 3; or is 4.
s is an integer from 0 to 2; or is 1; or is 0.
t1 is an integer from 0 to 3; or from 0 to 2; or is 0 or 1.
t2 is an integer from 0 to 3; or from 0 to 2; or is 0 or 1.
The compounds of the present invention typically exhibit selectivity for the human alpha 1a adrenergic receptor. One implication of this selectivity is that these compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure.
The compounds of this invention display submicromolar affinity for the human alpha 1a adrenergic receptor subtype while displaying lower affinity for the human alpha 1d and alpha 1b adrenergic receptor subtypes, and many other G-protein coupled human receptors. One class of the compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha 1a adrenergic receptor subtype while displaying at least about 10 fold lower affinity for the human alpha 1d and alpha 1b adrenergic receptor subtypes, and many other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors). In a subclass of the preceding class, the compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha 1a adrenergic receptor subtype while displaying at least about 100 fold lower affinity for the human alpha 1d and alpha 1b adrenergic receptor subtypes, in addition to exhibiting selectivity over other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors).
These compounds are administered in dosages effective to antagonize the alpha 1a receptor where such treatment is needed; e.g., treatment of BPH. For use in medicine, the salts of the compounds of this invention refer to non-toxic xe2x80x9cpharmaceutically acceptable salts.xe2x80x9d Other salts may, however, be useful in the preparation of the compounds according to the invention or in the prepartion of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following:
Acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate hydrobromide, hydrochloride, hydroxynaphthoate, hydroiodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, n-methylglucamine ammonium salt, oleate, palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, tosylate and valerate.
Compounds of this invention are used to reduce the acute symptoms of BPH. Thus, compounds of this invention may be used alone or in combination with more long-term anti-BPH therapeutics, such as testosterone 5-a reductase inhibitors, including PROSCAR(copyright) (finasteride). Aside from their utility as anti-BPH agents, these compounds may be used to induce highly tissue-specific, localized alpha 1a adrenergic receptor blockade whenever this is desired. Effects of this blockade include reduction of intraocular pressure, control of cardiac arrhythmias, and possibly a host of alpha 1a receptor mediated central nervous system events.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term xe2x80x9cadministeringxe2x80x9d shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
The present invention further includes metabolites of the compounds of the present invention. Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
Where the compounds according to the invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more chiral centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also encompassed within the scope of this invention.
The term xe2x80x9cselective alpha 1a adrenergic receptor antagonist,xe2x80x9d as used herein, refers to an alpha 1a antagonist compound which exhibits selectivity (e.g., at least about ten fold selectivity) for the human alpha 1a adrenergic receptor as compared to the human alpha 1b, alpha 1d, alpha 2a, alpha 2b and alpha 2c adrenergic receptors.
The term xe2x80x9clower urinary tract tissue,xe2x80x9d as used herein, refers to and includes, but is not limited to, prostatic smooth muscle, the prostatic capsule, the urethra and the bladder neck.
The term xe2x80x9csubject,xe2x80x9d as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
The present invention includes pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
As used herein, the term xe2x80x9ccompositionxe2x80x9d encompasses a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.
The specificity of binding of compounds showing affinity for the alpha 1a receptor is shown by comparing affinity to membranes obtained from transfected cell lines that express the alpha 1a receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., alpha 1d, alpha 1b) or beta adrenergic receptors. Expression of the cloned human alpha 1d, alpha 1b, and alpha 1a receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities. Antagonism by these compounds of the human alpha 1a adrenergic receptor subtype may be functionally demonstrated in anesthetized animals. These compounds may be used to increase urine flow without exhibiting hypotensive effects.
The ability of compounds of the present invention to specifically bind to the alpha 1a receptor makes them useful for the treatment of BPH. The specificity of binding of compounds showing affinity for the alpha 1a receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors. The human alpha adrenergic receptor of the 1a subtype was recently identified, cloned and expressed as described in PCT International Application Publication Nos. WO 94/08040, published Apr. 14, 1994 and WO 94121660, published Sep. 29, 1994. The cloned human alpha 1a receptor, when expressed in mammalian cell lines, is used to discover ligands that bind to the receptor and alter its function. Expression of the cloned human alpha 1d, alpha 1b, and alpha 1a receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.
Compounds of this invention exhibiting human alpha 1a adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions. [See e.g., PCT International Application Publication No. WO 94/10989, published May 26, 1994; U.S. Pat. No. 5,403,847, issued Apr. 4, 1995]. Compounds which are both selective amongst the various human alpha1 adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha 2 adrenergic receptors, the xcex2-adrenergic receptors, the muscarinic receptors, the serotonin receptors, the histamine receptors, and others are particularly preferred. The absence of these non-specific activities may be confirmed by using cloned and expressed receptors in an analogous fashion to the method disclosed herein for identifying compounds which have high affinity for the various human alpha1 adrenergic receptors. Furthermore, functional biological tests are used to confirm the effects of identified compounds as alpha 1a adrenergic receptor antagonists.
The present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention. The compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alpha 1a adrenergic receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration. For example, the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an alpha 1a antagonistic agent.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug""s availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as xe2x80x9ccarrierxe2x80x9d materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. Other dispersing agents which may be employed include glycerin and the like.
For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl-amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl-eneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha 1a adrenergic receptor is required.
The daily dosage of the products may be varied over a wide range; e.g., from about 0.01 to about 1000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0 and 100 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 20 mg/kg of body weight per day. Preferably, the range is from about 0.001 to about 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to about 7 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.
Compounds of this patent disclosure may be used alone at appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human alpha 1a adrenergic receptor while minimizing any potential toxicity. In addition, co-administration or sequential administration of other agents which alleviate the effects of BPH is desirable. Thus, in one embodiment, this invention is administration of compounds of this invention and a human testosterone 5-a reductase inhibitor. Included with this embodiment are inhibitors of 5-alpha reductase isoenzyme 2. Many such compounds are now well known in the art and include such compounds as PROSCAR(copyright), (also known as finasteride, a 4-Aza-steroid; see U.S. Pat. Nos. 4,377,584 and 4,760,071, for example). In addition to PROSCAR(copyright), which is principally active in prostatic tissue due to its selectivity for human 5-a reductase isozyme 2, combinations of compounds which are specifically active in inhibiting testosterone 5-alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes 1 and 2, are useful in combination with compounds of this invention. Compounds that are active as 5a-reductase inhibitors have been described in WO 93/23420, EP 0572166; WO 93/23050; WO 93/23038; WO 93/23048; WO 93/23041; WO 93/23040; WO 93/23039; WO 93/23376; WO 93/23419; EP 0572165; and WO 93/23051.
The dosages of the alpha 1a adrenergic receptor and testosterone 5-alpha reductase inhibitors are adjusted when combined to achieve desired effects. As those skilled in the art will appreciate, dosages of the 5-alpha reductase inhibitor and the alpha 1a adrenergic receptor antagonist may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term xe2x80x9cadministeringxe2x80x9d is to be interpreted accordingly.
Thus, in one embodiment of the present invention, a method of treating BPH is provided which comprises administering to a subject in need of treatment any of the compounds of the present invention in combination with finasteride effective to treat BPH. The dosage of finasteride administered to the subject is from about 0.01 mg per subject per day to about 50 mg per subject per day in combination with an alpha 1a antagonist. In one aspect, the dosage of finasteride in the combination is from about 0.2 mg per subject per day to about 10 mg per subject per day, and, in another aspect, from about 1 to about 7 mg per subject to day (e.g., about 5 mg per subject per day).
For the treatment of benign prostatic hyperplasia, compounds of this invention exhibiting alpha 1a adrenergic receptor blockade can be combined with a therapeutically effective amount of a 5a-reductase 2 inhibitor, such as finasteride, in addition to a 5a-reductase 1 inhibitor, such as 4,7xcex2-dimethyl-4-aza-5a-cholestan-3-one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation. Alternatively, a combined therapy can be employed wherein the alpha 1a adrenergic receptor antagonist and the 5a-reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Pat. Nos. 4,377,584 and 4,760,071 which describe dosages and formulations for 5a-reductase inhibitors.
Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows:
AcOH=acetic acid
Boc or BOC=t-butyloxycarbonyl
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene
DHP=dihydropyrimidinone
DIBAH=diisobutyl aluminum hydride
DIEA=diisopropylethylamine
DMF=N,N-dimethylformamide
DMSO=dimethylsulfoxide
EDC=1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EDTA=ethylenediamine tetraacetic acid
Et=ethyl
Et3N=triethylamine
Et2O=diethyl ether
EtOAc=ethyl acetate
EtOCOCl=ethylcbloroformate
FAB MS=fast atom bombardment mass spectroscopy
HOBt=1-hydroxy benzotriazole hydrate
HPLC=high performance liquid chromatography
LDA=lithium diisopropyl amide
LHMDA=lithium hexamethyldisilyl amide (or lithium hexamethyldisilazide)
mCPBA=m-chloroperbenzoic acid
m.p.=melting point
Me=methyl
MeOH=methanol
NCS=N-chlorosuccinimide
NMR=nuclear magnetic resonance
OXA or Oxa=oxazolidinone
Ph=phenyl
(p-NO2Ph)OCOCl=p-nitrophenylchloroformate
Pr=propyl
TFA=trifluoroacetic acid
THF=tetrahydrofuran
TLC=thin layer chromatography
TMS=trimethylsilyl
The compounds of the present invention can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthetic procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. Furthermore, other methods for preparing compounds of the invention will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.
Compounds of the present invention can be prepared by the coupling of a suitable spirotricyclic-substituted azacycloalkane (e.g., azetidine, pyrrolidine, piperidine, hexahydro-1H-azepine, etc.) or spriotricyclic-substituted N-(aminoalkyl)azacycloalkane (e.g., xcfx89-(aminoalkyl)piperidine) with a suitable derivative or activated form of Qxe2x80x94H, as described more fully below.
Spirofluorene-based compounds of the present invention can be prepared in accordance with Scheme 1, wherein fluorene G1 is treated with a strong base (e.g., LHMDA, LDA, or sodium or potassium hydride) and then with N-Boc-bis-(2-chloroethyl)amine to form the Boc-protected spirofluorene piperidine G2, which is treated with acid (e.g., TFA in CH2Cl2 or HCl in cold EtOAc) to obtain spirofluorene piperidine G3. Other N-Boc-bis-(haloalkyl)amines can be used in place of N-Boc-bis(2-chloroethyl)amine to provide a wide range of other spirofluorene azacycloalkanes suitable for preparing compounds of the invention; i.e., Boc-protected amines of formula: 
can be used to obtain spirofluorenes of formula: 
Compounds of formula Qxe2x80x2xe2x80x94H (Qxe2x80x2=Q other than the reverse dihydropyrimidinone (iii)) can be alkylated with a suitable dihaloalkyl compound to give haloalkylated Qxe2x80x2 (e.g., N-haloalkyloxazolidinone), which can be coupled to G3 via N-alkylation to obtain G5. Alternatively, G3 can be alkylated with a Boc-protected haloalkylamine to afford G6, which can then be acylated with an activated version of Qxe2x80x2xe2x80x94H to obtain G7. The activated version of Qxe2x80x2xe2x80x94H (e.g., the p-nitrophenylchloroformate derivative of Qxe2x80x2xe2x80x94H) can be obtained by deprotonating Qxe2x80x2xe2x80x94H with a base such as LDA, LHMDA, NaH, KH, or butyllithium, and then reacting the deprotonated species with phosgene or a phosgene equivalent such as (p-NO2Ph)OCOCl. As still another alternative, carboxylated derivative Qxe2x80x3xe2x80x94COOH (Qxe2x80x3=Q of structure (iii); i.e., reverse DHP) can be coupled with G6 via amidation to obtain G7xe2x80x2.
Scheme 2 provides a procedure for preparing spirothioxanthene, 1-oxospirothioxanthene, and 1,1-dioxospirothioxanthene compounds of the invention, wherein thioxanthone G8 is reduced to thioxanthene G9 which is spiroalkylated with NaH and N-methyl bis-(chloroethyl)amine in DMSO to form G10 which is demethylated by procedures known in the art (e.g., treatment with chloroformate) to form G11. N-Methyl bis-(chloroethyl)amine can be replaced with amines of formula: 
to obtain a wide range of spirothioxanthenes suitable for preparing compounds of the invention. G11 can be oxidized by treatment with 1 or with 2 equivalents of m-chloroperbenzoic acid to give the oxo or dioxo derivatives G12 or G13 respectively. The dioxo derivative G13 can alternatively be prepared directly from G11 by oxidizing G11 with H2O2-acetic acid. Saponification of G11, G12, or G13 with base provides the free amine G14, which can be coupled with a suitable derivative of Qxe2x80x94H to form compounds of the invention G15, G17, and G17xe2x80x2 using procedures analogous to those set forth in the description of Scheme 1 above.
Examples of spirothioxanthenepiperidines and their S-oxides and S,S-dixoides suitable for use in preparing compounds of the invention are described in U.S. Pat. No. 4,001,418.
Spiroxanthene, spiroazafluorene, and spirodibenzocycloheptane compounds of the invention can be prepared via in accordance with the procedures set forth in Schemes 3-5 respectively. Reduction of a xanthone derivative, e.g., 77, as illustrated in Scheme 3, provides the xanthene, e.g., 78, which may be spiroalkylated and elaborated to final products as described in preceding schemes and illustrated in Scheme 3. The xanthone 77 may be obtained as described by Granoth and Pownall, J. Org. Chem. 1975, 40: 2088-2091. N-methyl-spiroxanthenepiperidine itself (55), obtained as described by Galt et al., J. Med. Chem. 1989, 32: 2357-2362, may be converted to the 4-chloro- or 4,7-dichloro derivative by successive treatment with a chlorinating reagent, such as, for example, N-chlorosuccinimide. The product may be elaborated to final products using the procedures already described.
Spiropiperidine derivatives of azafluorenes may be prepared from the corresponding fluorenones as illustrated in Scheme 4. Thus, reduction of the azafluorenones, e.g., 92, by, for example, the Wolff-Kishner procedure known in the art, provides the azafluorenes, e.g., 84 or 93, which may be elaborated to final products using the procedures described above. Azafluorenes and azafluorenones are prepared by procedures known in the art such as, for example, those described by Kloc et al., J. Prakt. Chem. 1977, 319: 959-967; DuPriest et al., J. Org. Chem. 1986, 51: 2021-2023; Mayor and Wentrup, J. Am. Chem. Soc. 1975, 97: 7467-7480; Fuson and Miller, J. Am. Chem. Soc. 1957, 79: 3477-3480; Urbina, Syn. Comm. 9: 245-250; Wentrup et al., J. Org. Chem. 1978, 43: 2037-2041; Jutz et al., Liebigs Ann. Chem. 1975, 874-900; Braven et al., J. Het. Chem. 1995, 32: 1051-1055; and Hobson et al., J. Chem. Soc., 1924, 2365-2370; and references cited therein.
Spirodibenzocycloheptanepiperidine derivatives may be prepared as shown in Scheme 5. Thus, 5-cyano-5H-dibenzocycloheptanes such as 100 may be alkylated with, for example, N,N-dimethyl-2-chloroethane and strong base, such as lithium hexamethyldisilazide. The products may be reduced to aldehydes such as 102 with, for example, DIBAH. Examples of the alkylation of 5-cyano-5H-dibenzocycloheptanes and reduction to aldehydes are described by Ting et al., Bioorg. Med. Chem. Lett. 1995, 5: 2749-2754. The aldehydes may be condensed with 2-TMS-1,3-dithiane in the presence of base. With refluxing HCl/methanol, the thiane products are converted to thioate esters such as 104 which, upon reduction with, for example, LAH, afford hydroxyethyl derivatives such as 105. Conversion of the hydroxy group to halo by, for example, treatment with triphenylphosphine/carbon tetrachloride, and subsequent intramolecular alkylation to effect ring closure provides spirocyclic quaternary ammonium salts such as 106. Heating results in demethylation to tertiary amines such as 107, which may be again demethylated to the spiropiperidine and elaborated to final products using the procedures described above.
Qxe2x80x94H and derivatives suitable for use in the foregoing schemes can be prepared by procedures known to those of ordinary skill in the art. For example, unsubstituted, alkyl- and cycloalkyl-substituted oxazolidinones are prepared and activated in general by published and well developed chemistry, in particular, of Evans. See, e.g., Evans et al., xe2x80x9cStereoselective Aldol Condensationsxe2x80x9d in Topics in Stereochemistry (1982), 13: 1-115. The starting materials, in general, are natural and unnatural amino acids. For instance, some of the compounds are prepared from substituted phenyl glycine derivatives, which after reduction of the carboxylate and a phosgene equivalent mediated cyclization provides the substituted oxazolidinone ring system. Deprotonation with a strong base such as n-butyl lithium and addition to a phosgene or phosgene equivalent such as a THF solution of p-nitrophenylchloroformate produces the stable, isolable xe2x80x9cactivatedxe2x80x9d Oxa.
Oxazolidinones substituted with carboxylate, carboxamide, and alkoxyalkyl can be prepared by hydroxyamination of olefins to provide protected aminoalcohols, using procedures as described in G. Li et al., Angew. Chem. Int. Ed. Engl. (1996), 35: 2813-2817. Deprotection under standard conditions followed by a phosgene equivalent to mediate cyclization provides the substituted oxazolidinone ring system. Deprotonation with a strong base, for example, lithium bis(trimethylsilyl)amide, and addition to a THF solution of p-nitrophenylchloroformate (or other phosgene equivalent) produces the stable, isolable xe2x80x9cactivatedxe2x80x9d oxazolidinone.
Dihydropyrimidinones can be prepared by condensation reaction of the aldehyde, urea and a 1,3-acetoacetate type derivative catalyzed by a Lewis Acid, a copper (I) species and acetic acid. Activation can be accomplished by treatment with a strong base, for instance, LiN(TMS)2, followed by addition to a THF solution of p-nitrophenylchloroformate.
Hydantoins can be prepared in two chemical steps from ketones as outlined in the literature. More specifically, hydantoins can be prepared according to known methodology, such as described in J. J. Edmunds et al., J. Med. Chem. 1995, 38: 3759-3771, in J. H. Poupaert et al., J. Chem. Res. (S) 1979, 174-175, and in Chem. Rev. 1950, 46: 403-457.
Saccharins can be prepared according to known methods; e.g., page 40 and Examples 21 and 22 of PCT International Application Publication No. WO 96/25934, published Aug. 29, 1996.
The dihydropyrimidinones, oxazolidinones and hydantoins can be synthesized independently in racemic form, separated utilizing preparative chiral HPLC or other conventional procedures for separating optical isomers (e.g., resolution of diastereomeric salts), and then activated and reacted with the suitable spirotricyclic azacycles.
A general procedure for preparing reverse DHP intermediates is set forth in Scheme 6, wherein the methylproprionate C1 is condensed with urea C2 and arylaldehyde C3, catalyzed by acetic acid, copper oxide and a Lewis acid (e.g., BF3.Et2O) to obtain the 4-aryl-1,2,3,4-tetrahydropyrimidin-2-one-5-carboxylic acid methyl ester C4, which is subsequently converted to the 5-carboxylic acid derivative C6 by basic hydrolysis. Alternatively, the methyl ester can first be treated with an alkyl or cycloalkyl halide (e.g., an iodide such as methyl iodide) to obtain the 3-alkyl or 3-cycloalkyl derivative C5, which is then hydrolyzed to the 5-carboxylic acid derivative C7.
Reverse DHP optical isomers can be resolved by using preparative chiral HPLC. They can also be resolved by reacting a mixture of methyl ester enantiomers with LDA and p-nitrophenylchloroformate, followed by treatment with R-(+) alpha methyl benzylamine to obtain the 3-(1-phenylethyl-carbamoyl) diastereomers, which are separated by conventional means known in the art. The enantiomers are then obtained from the separated diastereomers first by reaction with DBU to regenerate the methyl ester (e.g., enantiomer of C4), followed directly by basic hydrolysis to obtain the corresponding carboxylic acid enantiomer (e.g., enantiomer of C6), or followed by reaction with an alkyl or cycloalkyl halide (to provide, e.g., an enantiomer of C5) and then hydrolysis to obtain the corresponding carboxylic acid enantiomer (e.g., enantiomer of C7). 